Oncogenic BRAF-Mediated Melanoma Cell Invasion

Summary Melanoma patients with oncogenic BRAF V600E mutation have poor prognoses. While the role of BRAF V600E in tumorigenesis is well established, its involvement in metastasis that is clinically observed in melanoma patients remains a topic of debate. Here, we show that BRAF V600E melanoma cells have extensive invasion activity as assayed by the generation of F-actin and cortactin foci that mediate membrane protrusion, and degradation of the extracellular matrix (ECM). Inhibition of BRAF V600E blocks melanoma cell invasion. In a BRAF V600E -driven murine melanoma model or in patients' tumor biopsies, cortactin foci decrease upon inhibitor treatment. In addition, genome-wide expression analysis shows that a number of invadopodia-related genes are downregulated after BRAF V600E inhibition. Mechanistically, BRAF V600E induces phosphorylation of cortactin and the exocyst subunit Exo70 through ERK, which regulates actin dynamics and matrix metalloprotease secretion, respectively. Our results provide support for the role of BRAF V600E in metastasis and suggest that inhibiting invasion is a potential therapeutic strategy against melanoma.